A number of diseases and conditions are believed to be associated with excessive 5- and/or 12-lipoxygenase activity. These include inflammation, arthritis, multiple sclerosis, diabetes, and coronary disease, as well as cancers, for example of the prostate, colon, pancreas, and lung.
Inflammation represents a cascade of physiological and immunological reactions that nature has designed as the first cellular response to noxious stimuli in an effort to localize toxic materials or prevent tissue injury. Clinically, inflammation is a primary disease under acute conditions or is a manifestation of underlying pathophysiological abnormalities in chronic disease, characterized by classic signs of redness, pain, swelling, and loss of function. Inflammatory diseases are a significant cause of morbidity and mortality in humans.
Arthritis is a disease that results in degradation and degeneration of the articular cartilage. The major symptoms of arthritis are pain, stiffness, crackling, and enlargement, and deformities of the affected joints, and, in some cases, these symptoms can be accompanied by inflammation and swelling of the joints. To ease the pain associated with arthritis, millions of people ingest daily high doses of non-steroidal anti-inflammatory drugs (“NSAIDs”), such as ibuprofen. Unfortunately, NSAIDs irritate the stomach and the intestines in many people causing ulcers and bleeding. It has been reported in the Archives of Internal Medicine that ulcers and gastrointestinal bleeding caused by NSAIDs lead to as many as 20,000 deaths each year.
Pancreatic cancer is one of the most enigmatic and aggressive malignant diseases facing oncologists (Parker et al., “Cancer Statistics. 1996,” CA Cancer J. Clin., 46:5-27 (1996) (“Parker”)). It is now the fourth leading cause of cancer death in both men and women in the United States, and the incidence of this disease has significantly increased over the past 20 years (Parker; Trede et al., “Survival After Pancreaticoduodenectomy: 118 Consecutive Resections Without an Operative Mortality,” Ann. Surq., 211:447-458 (1990); Cameron et al., “One Hundred and Forty-five Consecutive Pancreaticoduodenectomies Without Mortality,” Ann. Surg.,217:430-438 (1993); Horward, “Pancreatic Adenocarcinoma,” Curr. Prob. in Cancer, 20:286-293 (1996) (“Horward”); Poston et al., Gut. Biology of Pancreatic Cancer, 32:800-812 (1991) (“Poston”); and Black et al., “Treatment of Pancreatic Cancer: Current Limitations, Future Possibilities,” Oncology, 10:301-307 (1996) (“Black”)). Pancreatic cancer is responsible for 27,000 deaths per year in the United States. Because of lack of early diagnosis and poor therapeutic responsiveness of pancreatic cancer, less than 2% of patients survive beyond five years, and the median expectation of life after diagnosis of pancreatic cancer is less than 6 months (Horward; Poston; and Black).
Colonic cancer is the second most common form of cancer in the United States (Doll et al., “Mortality in Relation to Smoking: 20 Years' Observations on Male British Doctors,” BMJ, 2:1525-153.6 (1976); Hruban et al., “Molecular Diagnosis of Cancer and Micrometastases,” Adv. Anat. Pathol., 5:175-178 (1998) (“Hruban”); Figueredo et al., “Adjuvant Therapy for Stage II Colon Cancer After Complete Resection. Provincial Gastrointestinal Disease Site Group,” Cancer Prev. Control, 1:379-92 (1997) (“Figueredo”); Ness et al., “Outcome States of Colorectal Cancer: Identification and Description Using Patient Focus Groups,” Am. J. Gastroenterol., 93:1491-7 (1998) (“Ness”); Trehu et al., “Cost of Screening for Colorectal Cancer: Results of a Community Mass Screening Program and Review of Literature,” South Med. J., 85:248-253 (1992); and Wingo et al., “Cancer Statistics,” CA Cancer J. Clin., 45:8-30 (1995) (“Wingo”)). Colonic cancer occurs in more than 138,000 patients and is responsible for more than 55,000 deaths in the United States each year (Wingo). Up to 70% of patients with colonic cancer develop hepatic metastasises by the time of death, indicating that non-detectable micro-metastases are present at the time of surgery (Hruban; Figueredo; and Ness). Furthermore, metastatic cancer is often not responsive to standard chemotherapeutic regimens, resulting in treatment failure (Figueredo and Ness). The overall response of advanced or non-resectable colorectal cancer patients to chemotherapeutic agents varies from 26 to 44 percent. For example, less than one third of colorectal cancer patients with liver metastases respond to treatment with agents such as 5-FU and leucovorin (Id.).
Breast cancer has the highest incidence of any cancer in women with the diagnosis being made in more than 275,000 per year in the USA (Richards et al., “Influence of Delay on Survival in Patients with Breast Cancer: A Systematic Review,” Lancet, 353:1119-26 (1999); Norton, “Adjuvant Breast Cancer Therapy: Current Status and Future Strategies—Growth Kinetics and the Improved Drug Therapy of Breast Cancer,” Semin. Oncol., 26:1-4 (1999); Morrow et al., “Current Controversies in Breast Cancer Management,” Curr. Probl. Surg., 36:163-216 (1999); and Ruppert et al., “Gene Therapy Strategies for Carcinoma of the Breast,” Breast Cancer Res. Treatment, 44:93-114 (1997)). Even though five year survival has increased to more than 80%, more than 77,000 women still die from this disease each year (Id.).
Accordingly, there continues to be a need for agents and methods for treating pancreatic, colonic, and breast cancer as well as diseases and conditions that are believed to be associated with the inappropriate expression and/or activity of 5- and/or 12-lipoxygenases. The present invention is directed, in part, to meeting these needs.